Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colon cancer. However, the influence of diet and lifestyle factors on the outcome of patients with established colon cancer is virtually unknown. Randomized clinical trials demonstrate a significant survival advantage for individuals with stage III colon cancer who receive adjuvant fluorouracil- based chemotherapy. Nonetheless, 40-45% of stage III patients receiving current adjuvant chemotherapy will develop metastases. Patients often seek to understand what, if any, diet and lifestyle will reduce their chances of cancer recurrence beyond standard surgery and post-operative adjuvant therapy. Moreover, how diet and lifestyle influence prognosis may depend, in part, on molecular characteristics of the tumor. During the previous funding period, we found that relative states of hyperinsulinemia and insulin resistance, including a history of type 2 diabetes, obesity, sedentary lifestyle, high intake of a Western pattern diet, high dietary glycemic load, and elevated plasma C-peptide conferred an increased risk of colon cancer recurrence. Additionally, recognizing the intersection of nutrient excess and derangements in cellular and molecular mediators of inflammation, we concurrently found that regular aspirin or selective COX-2 inhibitor use was associated with reduced cancer recurrence and mortality. In this competitive renewal application, (Aim 1) we propose to identify novel dietary and lifestyle risk factors for CRC recurrence and mortality, and, moreover, identify potential mechanisms of action through detailed, hypothesis-based molecular analysis of patient tumors. Additionally, recognizing that energy excess and insulin resistance may alternatively drive cancer recurrence through promotion of inflammation-related pathways, (Aim 2) we will further assess the role of anti- inflammatory medications to abrogate the increased risk of cancer recurrence associated with energy excess. Finally, (Aim 3) we will combine the available data to develop a novel comprehensive dietary risk prediction model for cancer recurrence and mortality, incorporating dietary/lifestyle factors with established clinical- pathologic covariates, and validate the model n 3 independent CRC patient cohorts to provide a more robust risk assessment tool for newly diagnosed CRC patients that can meaningfully inform clinical care and potentially incorporate lifestyle modification into CRC treatment recommendations. Many hypotheses would be interesting on their own, but the most unique strength of this proposal is our ability to assess simultaneously diet, medication, lifestyle factors, and molecular alterations in tumor tissue. Ultimately, we believe the proposed work will advance our understanding of CRC biology, identify interventions that can improve patient survival, and, with the extensive clinical, pathologic, and biomarker data available for analysis, inform clinicians how to maximally utilize these interventions to improve clinical care.
While considerable evidence supports the role of diet and lifestyle on the risk of developing colorectal cancer, the effect that these factors play on the survival of patients with established colorectal cancer is largely unknown. Using the resources of a large clinical trial, we propose to define the influence of these factors on patient survival o provide valuable information on colorectal cancer biology and offer meaningful interventions to improve patient outcomes.
Showing the most recent 10 out of 91 publications
